JP5800417B2 - External patch - Google Patents

Description

  The present invention relates to a patch containing loxoprofen sodium, an organic acid, and aluminum glycinate. More specifically, it contains loxoprofen sodium, an organic acid as a main agent solubilizer, and aluminum glycinate as a stabilizer for loxoprofen sodium. The present invention relates to an external patch.

  Loxoprofen sodium is a drug that exhibits excellent anti-inflammatory and analgesic effects as a non-steroidal antiphlogistic analgesic based on phenylpropionic acid, and has been studied for formulation as a patch regardless of whether it is aqueous or oily. Already, poultices (brand name: Loxonin Papp) and plaster drugs (brand name: Loxonin Tape) are already on the market.

  When non-steroidal anti-inflammatory analgesics such as loxoprofen sodium are formulated in oily patches, the formulation of various solubilizers has been studied in order to stably dissolve loxoprofen sodium in the oily base. Yes. For example, Patent Document 1 describes a plaster agent containing crotamiton as a solubilizer. Patent Document 2 describes a plaster agent containing pyrrolidone such as N-methyl-2-pyrrolidone as a solubilizer. Further, Patent Document 3 describes a plaster agent containing an aliphatic hydroxy acid and a higher fatty acid.

  Organic acid, particularly lactic acid which is liquid at room temperature, is a good solvent for loxoprofen sodium, but lactic acid may react with loxoprofen sodium in the preparation to produce a decomposition product of loxoprofen sodium. Therefore, when loxoprofen sodium is blended in an oily base blended with an organic acid such as lactic acid, it is necessary to suppress the formation of decomposition products.

  Attempts have also been made to increase the stability of drugs in preparations for oily patches containing loxoprofen sodium. For example, Patent Document 4 describes an external patch containing a fatty acid metal salt such as zinc stearate or aluminum stearate, and suppresses the esterification reaction of L-menthol and a drug to be used in combination with the fatty acid metal salt. It has been shown that it can.

  In addition, an external patch containing a metal carbonate (Patent Literature 5), an external patch containing a metal oxide (Patent Literature 6), and an external patch containing a metal hydroxide (Patent Literature 7) ) Are proposed, but the oily patch containing the metal salt or metal compound shown here is a decomposition product produced by an esterification reaction occurring between L-menthol and loxoprofen sodium used together. However, the effect of inhibiting decomposition products produced by the reaction between the organic acid and loxoprofen sodium was not sufficient.

JP 2004-043512 A JP 2008-163017 A JP 2011-20997 A International Publication No. WO96 / 08245 JP 2010-90098 A JP 2002-226366 A JP 2005-314328 A

  Therefore, the present invention solves the above problems, and in an external patch containing an organic acid and loxoprofe sodium, it is possible to suppress the production of a decomposition product of loxoprofe sodium derived from the blending of the organic acid. An object is to provide an external patch having high stability.

  As a result of intensive studies in order to solve the above-mentioned problems, the present inventor, by blending aluminum glycinate, which is usually used as a crosslinking agent such as a poultice, in an adhesive base, The present inventors have found that the production of decomposition products generated by the reaction of Loxoprofen with Loxoprofen can be suppressed.

  That is, the basic aspect of the present invention is an external patch characterized by containing loxoprofen sodium, an organic acid, and aluminum glycinate.

  More specifically, it is an external patch in which the amount of the aluminum glycinate is 0.001 to 5% by weight, and the external patch in which the organic acid is lactic acid.

The patch for external use provided by the present invention suppresses the formation of decomposition products generated by the reaction of loxoprofen sodium with an organic acid by the action of the aluminum glycinate to be blended.
Therefore, according to the present invention, it is possible to provide a loxoprofen sodium-containing external patch having high stability of the main drug.

It is the figure which showed the fixed_quantity | quantitative_assay result of the decomposition product 1 of a test example. It is the figure which showed the fixed_quantity | quantitative_assay result of the decomposition product 2 of a test example.

In the external patch of the present invention, the blending amount of loxoprofen sodium in the preparation is not particularly limited as long as it can be formulated, but is preferably 0.1 to 10% by weight based on the total weight of the preparation. Preferably, it is blended in the range of 0.5 to 6% by weight.
If the loxoprofen sodium content in the preparation is less than 0.1% by weight, the transdermal absorbability is insufficient, and if it exceeds 10% by weight, not only the physical properties of the patch are impaired, but also economically disadvantageous. It is not preferable.

  The organic acid blended in the present invention functions as a solubilizer for loxoprofen sodium. Examples of organic acids that can be used include acetic acid, propionic acid, isobutyric acid, caproic acid, caprylic acid, lactic acid, maleic acid, pyruvic acid, oxalic acid, succinic acid, tartaric acid, malic acid, and glycolic acid. it can. Among them, it is preferable to use lactic acid in consideration of the solubility of loxoprofen sodium.

  The amount of organic acid is 0.01 to 10.0% by weight, preferably 0.3 to 5% by weight, more preferably 0.3 to 3% by weight, although it depends on the amount of loxoprofen sodium as the main agent. It is good to mix in the range of. If the amount of the organic acid is less than 0.01% by weight, it is impossible to sufficiently dissolve loxoprofen sodium in the adhesive base, and the percutaneous absorbability of the preparation is reduced, or the active ingredient in the preparation during storage If crystal precipitation occurs and the amount of the organic acid exceeds 10% by weight, there are problems such as an increase in the amount of decomposition products, skin irritation, and physical properties of the preparation. Arise.

  The amount of aluminum glycinate compounded in the external patch of the present invention is 0.001 to 5% by weight, preferably 0.005 to 3% by weight. If it is less than 0.001% by weight, the effect of inhibiting the generation of the decomposition product is insufficient, and conversely, even if it exceeds 5% by weight, no further effect is seen. The physical properties of deteriorate.

  In addition to the base polymer, a tackifier resin, a softener, and other additives can be blended in the adhesive base of the external patch of the present invention.

  As the base polymer used in the external patch of the present invention, an acrylic pressure-sensitive adhesive, a rubber-based pressure-sensitive adhesive, a silicon-based pressure-sensitive adhesive, and the like can be used, but it is preferable to use a rubber-based pressure-sensitive adhesive. Examples of rubber-based adhesives include natural rubber, polyisoprene, polybutadiene, styrene-isoprene-styrene block copolymer, styrene-butadiene rubber, and styrene-isoprene rubber, but styrene-isoprene-styrene block copolymer is used. Is preferred. The blending amount of the styrene-isoprene-styrene block copolymer (hereinafter referred to as SIS) is determined in consideration of the blending amount of other components, but is usually 5 to 30% by weight, preferably 10 to 25% by weight. % Blended. When the blending amount is less than 5% by weight, the cohesive strength and shape retention of the base are lowered. On the other hand, when the above blending amount exceeds 30% by weight, the adhesive strength decreases, the plaster becomes uneven, and the workability in the manufacturing process decreases.

  The tackifying resin is not particularly limited as long as it is generally blended in a patch, for example, a rosin resin such as rosin ester and hydrogenated rosin glycerin ester, an alicyclic saturated hydrocarbon resin, etc. Examples include petroleum resins and terpene resins. The amount of tackifying resin is not particularly limited as long as it can be formulated, but it is preferably blended in the range of 10 to 50% by weight based on the total weight of the formulation. More preferably, it is 15 to 40% by weight. If the content of the tackifying resin in the preparation is less than 10% by weight, the adhesive strength is weak, causing a problem of peeling off during sticking. If the content exceeds 50% by weight, the adhesive strength of the preparation is conversely strong. This is not preferable because it causes problems such as excessive skin irritation and skin irritation.

  The softener used in the external patch of the present invention has good compatibility with other base components and gives flexibility to the base. Polyisobutylene, liquid polyisoprene, polybutene, lanolin, castor oil, Examples include almond oil, olive oil, camellia oil, persic oil, peanut oil, process oil, extender oil, and liquid paraffin. Preferred are polybutene and liquid paraffin. The softeners can be used alone or in combination of two or more. The blending amount of the softening agent is determined in consideration of the blending amount of other liquid components blended in the preparation, but is usually 10 to 75% by weight, preferably 15 to 50% by weight.

  In the pressure-sensitive adhesive layer of the external patch of the present invention, a solubilizer and other absorption promoters can be blended as necessary. These solubilizers or absorption promoters include fatty acid esters such as isopropyl myristate, diethyl sebacate, diisopropyl sebacate, diisopropyl adipate, isopropyl palmitate, and polyvalent polyols such as propylene glycol, polyethylene glycol, butylene glycol, and glycerin. Examples include pyrrolidone compounds such as alcohol, N-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, N-octyl-2-pyrrolidone, crotamiton, and other various surfactants.

  In the external patch of the present invention, various base components used in normal external patches can be used as long as they do not affect others. The base component is not particularly limited, but water-soluble polymers such as polyvinyl pyrrolidone, polyvinyl alcohol, and polyacrylic acid; cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, mint oil, and refreshment such as L-menthol. Agent, silicon compound such as silicic anhydride, light anhydrous silicic acid, dibutylhydroxytoluene, pentaerythrityl-tetrakis [3- (3,5-di-t-butyl-4-hydroxyphenyl) propionate], tocopherol acetate, Examples include antioxidants such as ascorbic acid; inorganic fillers such as zinc oxide, aluminum oxide, titanium dioxide, silicas, magnesium oxide, iron oxide, and zinc stearate. Further, preservatives, bactericides, flavoring agents, coloring agents, and the like can be added as necessary.

  Examples of the support for the external patch include films, nonwoven fabrics, knitted fabrics, and laminate composites of nonwoven fabrics and films. Examples of materials for these supports include polyethylene, polypropylene, polyvinyl chloride, polyester, polyethylene terephthalate, nylon, polyurethane, rayon, polyacrylonitrile, polystyrene, and polyethylene naphthalate.

  Polyethylene terephthalate, polypropylene, paper or the like can be used as the release liner used for the external patch, and polyethylene terephthalate is particularly preferable. The release liner may be siliconized as necessary to optimize the release force.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated more concretely, this invention is not limited to a following example.

[Example]
SIS (Quintac 3570C; Nippon Zeon), alicyclic saturated hydrocarbon resin (Arcon P-100; Arakawa Chemical Industries), polybutene (HV-300F; JX Nippon Mining & Energy), liquid paraffin (Hicoll M-352; Kaneda) ) And BHT (dibutylhydroxytoluene) were dissolved by stirring under heating in a nitrogen atmosphere. Subsequently, loxoprofen sodium, L-menthol, lactic acid, and aluminum glycinate, which are the main agents, were added to the pressure-sensitive adhesive, and further stirred and mixed to prepare a pressure-sensitive adhesive.
The prepared pressure-sensitive adhesive was coated on a silicon-treated polyethylene terephthalate film to form a pressure-sensitive adhesive layer having a thickness of about 150 μm. The obtained adhesive layer was laminated to a polyester woven fabric as a support to obtain an external patch of the present invention. The amount of each component is shown in Table 1 below.

[Comparative Examples 1-2]
Each composition for external use of Comparative Examples 1 and 2 was obtained according to the same production method as in the Examples with the composition shown in Table 1 below.

  Unit:% by weight

Test example: Stability test (quantitative test of degradation products)
About the formulation of Example obtained above and Comparative Examples 1-2, it preserve | saved on the preservation | save temperature condition of 60 degreeC, and the amount of degradation products in the preservation | save sample (formulation) in each preservation | save period of 0, 1, and 3 months ( (Production amount%) was measured.
The sample preparation method and HPLC measurement conditions are shown below.
In addition, as a degradation product derived from an organic acid, a degradation product (hereinafter referred to as a degradation product) detected at a relative retention time of 1.55 to 1.60 when the retention time of loxoprofen sodium is 1 under the HPLC measurement conditions shown below. , And a decomposition product (hereinafter referred to as decomposition product 2) detected at a relative retention time of 1.65 to 1.70, the amount of the product was measured.
The quantitative result of the decomposition product 1 is shown in FIG. 1, and the quantitative result of the decomposition product 2 is shown in FIG.

[Sample preparation method]
Each preparation was punched into a size of 5 × 7 cm ² , tetrahydrofuran (hereinafter referred to as THF) was added, and ultrasonic extraction and extraction with a shaker were performed. The obtained extract was made up to 100 mL with THF to obtain an extract. 3 mL of this extract was taken, made up to 50 mL with 40% acetonitrile, filtered using a membrane filter (0.45 μm), and the resulting solution was used as a test sample.

[HPLC measurement conditions]
Column: Unison UK-C18 (3 x 150 mm)
Mobile phase: acetonitrile: water: phosphoric acid = 400: 600: 1
Flow rate: 0.5 mL / min Wavelength: 223 nm
Injection volume: 10 μL

  As is clear from the results shown in FIG. 1 and FIG. 2, in each comparative example, the amount of decomposition products derived from organic acids increased with time, whereas the preparation of the examples of the present invention In, the production of decomposition products is greatly suppressed.

[Specific Formulation Examples 1 to 9]
Tables 2 and 3 below show specific formulation examples 1 to 9 other than the external patch of the present invention shown in the above examples. The unit is% by weight.
However, the present invention is not limited to this.

As described above, the external patch provided by the present invention suppresses the production of decomposition products generated by the reaction of loxoprofen sodium with an organic acid by the action of the aluminum glycinate to be blended, A loxoprofen sodium-containing external patch with stability is provided.
The external patch provided by the present invention is, for example, osteoarthritis, rheumatoid arthritis, low back pain, shoulder periarthritis, tendonitis, peritonitis, humerus condylaritis (tennis elbow etc.), muscle pain, trauma It is useful for the prevention and treatment of later swelling and pain.

Claims (2)

A patch for external use comprising loxoprofen sodium, lactic acid , and aluminum glycinate.   The external patch according to claim 1, wherein the amount of the aluminum glycinate is 0.001 to 5% by weight.

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